TY - JOUR
T1 - Delivering AMPA Receptors to the Synapse
JF - Science's STKE
JO - Sci. STKE
SP - tw439
LP - tw439
DO - 10.1126/stke.4152007tw439
VL - 2007
IS - 415
AU - Gough, Nancy R.
Y1 - 2007/12/04
UR - http://stke.sciencemag.org/content/2007/415/tw439.abstract
N2 - Incorporation of AMPA-type glutamate receptors containing the GluR1 subunit into the postsynaptic membrane is associated with long-term potentiation (LTP), a form of synaptic plasticity that may underlie some forms of memory. The trafficking of GluR1-containing receptors to the cell surface is regulated by multiple interactions that occur with the C-terminal domain (CTD), including interactions with kinases that phosphorylate the CTD. Phosphorylation of Ser845, reportedly mediated by the adenosine 3′,5′-monophosphate (cAMP)-regulated enzyme protein kinase A (PKA), appears to be required for GluR1 synaptic insertion. Serulle et al. provide evidence that Ser845 can also be phosphorylated by guanosine 3′,5′-monophosphate (cGMP)-dependent protein kinase II (cGKII), thereby providing a mechanism for nitric oxide signaling downstream of NMDA-type glutamate receptors to increase synaptic strength and contribute to LTP. cGKII was identified in a modified yeast two-hybrid screen for proteins that interacted with the CTD of GluR1. In vitro binding studies suggested that activation of cGKII (binding to the cGMP analog 8-Br-cGMP) increased its interaction with the GluR1 CTD. In lysates from rat brain, cGKII and GluR1 were present in the same subcellular fraction and coimmunoprecipitated. In cultured hippocampal neurons, endogenous cGKII and GluR1 colocalized and coimmunoprecipitated. The interaction was enhanced when the cells were (i) exposed to 8-Br-cGMP to stabilize cGKII in the active conformation, (ii) exposed to glycine to induce a chemical form of LTP (chemLTP) that involves activation of NMDA receptors and activation of nitric oxide synthase and soluble guanylate cyclase (the enzyme that produces cGMP), or (iii) exposed to a nitric oxide donor. In vitro kinase assays demonstrated that the GluR1 CTD was phosphorylated by cGKII at Ser845, the same site phosphorylated by PKA. In cultured neurons, chemLTP also triggered phosphorylation of GluR1 at Ser845, and this was blocked by the presence of an NMDA receptor antagonist or cGKII inhibitor. Both cAMP analogs and cGMP analogs increased the abundance of GluR1 at the surface of hippocampal neurons but did not induce LTP. The chemLTP condition stimulated an increase in synaptic GluR1 and induced LTP, which was measured as a sustained increase in miniature excitatory postsynaptic currents. The interaction of GluRI with PKA is indirect, requiring the PDZ scaffolding protein SAP97. The interaction with cGKII appears to be direct and involves Arg837 and does not require SAP97 as a mediator. With mutants either lacking the SAP97 binding region or containing a point mutation at Arg837, the authors demonstrated that the cAMP- and cGMP-mediated GluR1 trafficking and phosphorylation pathways were independent. In hippocampal mouse slices, pharmacological inhibitors of the NO to cGMP pathway or expression of a dominant-negative fragment of the cGKII that disrupted the interaction between cGKII and GluR1 inhibited LTP in response to tetanic stimulation. Thus, it appears that both cAMP and cGMP pathways converge on Ser845 to regulate GluR1 trafficking. Y. Serulle, S. Zhang, I. Ninan, D. Puzzo, M. McCarthy, L. Khatri, O. Arancio, E. B. Ziff, A GluR1-cGKII interaction regulates AMPA receptor trafficking. Neuron 56, 670-688 (2007). [PubMed]
ER -